JPH09227385A - Adjuvant for ophthalmic operation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the above adjuvant, comprising an aqueous solution of hyaluronic acid, having a medium viscosity containing a specific viscosity stabilizer, excellent in long term-storage stability at ambient temperature and capable of preventing viscosity-lowering even under an ordinary condition of heat pasteurization. SOLUTION: This adjuvant includes (A) hyaluronic acid and/or the solt and (B) a polycarbonic acid or the soil (preferably sodium citrate, carboxyvinyl polymer), a polyol (preferably ethylene glycol, glycerin, etc.), a saccharide (preferably solbitol, trehalose, etc.) and a viscosity stabilizer selecting from an amino acid and the solt (preferably histidine, arginine etc.) and consists of an aqueous solution having a viscosity of 2000-20,000 centipoise at 37 deg.C. Sodium sat is preferable as the hyaluronic acid salt. Moreover, a blending amount of the component B is preferable to be each 0.05-1(weight)% in the case that the component B is a polycarbonic acid and the salt or an amino acid, 1-2.5% in case of the polyol and 0.05-5% in the case of the saccharide.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an auxiliary for eye surgery such as cataract surgery, intraocular lens transplantation surgery, glaucoma surgery and full-thickness corneal transplantation surgery. More specifically, it relates to an auxiliary agent for eye surgery, which is relatively stable at room temperature and under heating.

[0002]

[Prior Art] In recent years, the number of patients with various eye diseases has increased along with the increase of the elderly, and the development of effective pharmacotherapy methods and simple and safe surgical methods will continue to be increasingly important in the future. Become. Among them, the development of new surgical modalities of cataract surgery, intraocular lens insertion surgery and glaucoma surgery has made remarkable progress year by year, and has become a gospel for patients. In cataract surgery, by using a technique such as ultrasonic emulsification suction for crushing and removing the opaque lens, the operation is simplified, the incision site is reduced, the intraocular lens is improved, and the insertion is advanced. The course is improved, and as a result,
Day surgery was also possible.

In order to carry out the above-mentioned operation smoothly and safely, a viscoelastic substance used as an auxiliary agent for operation plays an important role. That is, during surgery, by injecting the surgical auxiliary agent into the eye through the incision site, space maintenance of the anterior chamber and posterior chamber, protection of tissues and endothelial cells from mechanical trauma, easy operation of surgical instruments and intraocular lens Insert,
Effects such as minimizing bleeding are obtained. Hyaluronic acid or its salts, chondroitin sulfate or its salts, methylcellulose, etc. are currently used clinically as the main components of these surgical adjuvants. Among them, an aqueous solution of sodium hyaluronate is particularly used as a main component of the viscoelastic preparation because it has high viscoelasticity necessary for maintaining an intraocular space and has biosafety.

The chemical structure of sodium hyaluronate consists of sodium glucuronate and N-acetylglucosan β1.
It is a high molecular polysaccharide having repeating units of → 3 and β1 → 4 bonds. The substance is distributed in mammalian cartilage, connective tissues such as joints, the vitreous body of the eye, and the corolla. In recent years, the substance can be obtained by producing microorganisms such as Streptococcus. Natural sodium hyaluronate is
When present in a living body, its average molecular weight is 8,000,000 to 1
It is said to be 3 million, and its molecular weight range is usually 20,000-40 because it undergoes lower molecular weight one after another during its isolation and purification.
100,000 products will be available.

The molecular weight range of this substance currently clinically used for ophthalmic surgery is high molecular weight (1.9 million to 390).
10,000), medium molecular weight (1.5 to 2.1 million) and low molecular weight (600 to 1.2 million). Clinical evaluation has both advantages and disadvantages due to the difference in these molecular weights. Among these, medium-viscosity preparations composed of low or medium molecular weight sodium hyaluronate, compared with the corresponding high-viscosity preparations of high molecular weight, reduce postoperative elevation of intraocular pressure and inflammation, and the speed of recovery. However, there are many advantages such as low endothelial cell reduction rate. On the other hand, the drawbacks of the medium viscosity preparation are said to be inferior in intraocular space forming power and inhalation removal property of used preparation from the eye ( Su.
rv. Ophthalmol ., 34, 268, 1990 and ophthalmic surgery, 6, 459, 1993).

The powdery substance, when used for the above-mentioned purpose, must be dissolved in physiological saline, phosphoric acid, boric acid and Tris buffer. However, the hyaluronic acid in such an aqueous solution state is gradually degraded at room temperature and rapidly under heating conditions, and the viscosity (or intrinsic viscosity) is also reduced accordingly. Therefore, most of the products on the market have to be stored in a cool and dark place for a long period of time, and the labor and distribution cost at the time of product distribution cannot be ignored. Further, the heat sterilization operation, which is important in the formulation process, is complicated, such as the intermittent sterilization method, and many precautions are required to prevent lowering of the molecular weight of the main component.

Regarding the method for stabilizing an aqueous solution of sodium hyaluronate, a method of allowing a compound having a phenolic hydroxyl group to coexist (see JP-A-1-113401) and a method of adding a polymer such as polyamino acid or polyacrylic acid (See JP-A-57-185208), the viscosity of the preparation is 100 centipoise (cp).
It was as low as less than s), and satisfactory results were not obtained for both stability and viscosity. Furthermore, it is known that polyhydric alcohols, monosaccharides and sugar alcohols are added to an aqueous solution of hyaluronic acid as other viscosity stabilizers and applied to cosmetics and cosmetic lotions (JP-A-55-1537).
No. 11 and JP-A-61-180705).

Further, a highly viscous aqueous solution preparation containing 20,000 to 200,000 centipoise and containing a non-electrolyte selected from the group consisting of polyhydric alcohols, sugar alcohols, glucose and mannose and hyaluronate is also known. 1-
22248). As described in the same publication, this preparation is a highly viscous preparation to prevent damage to the tissue surface during anterior segment surgery, and to safely and reliably perform procedures such as suturing and post-operative surgery. To prevent adhesions.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide an auxiliary for eye surgery. Another object of the present invention is to provide an ophthalmic surgery adjunct, which comprises a stable medium-viscosity preparation of a hyaluronic acid aqueous solution. Still another object of the present invention is to provide an ophthalmic adjuvant which is excellent in storage stability over a long period of time at room temperature and which can prevent a decrease in viscosity even under ordinary heat sterilization conditions. . Still another object of the present invention is to enhance the relatively low intraocular space forming ability by containing a thickener (viscosity stabilizer), and to take advantage of the ophthalmologic clinical advantage of the low molecular weight hyaluronic acid preparation. To provide an eye surgery adjunct. Further objects and advantages of the present invention will be apparent from the following description.

[0010]

The inventors of the present invention have conducted a search for a stabilizer to solve the above problems, and as a result, have found that an aqueous solution containing hyaluronic acid or a salt thereof contains a specific polycarboxylic acid or polyol. It has been found that the addition of sugars and amino acids suppresses the lowering of viscosity of the aqueous solution, and exhibits viscosity stability at room temperature and under heating for a long period of time, and the stabilizer also has a thickening effect. Therefore, a thickened preparation of a low molecular weight hyaluronic acid aqueous solution was prepared, and the present invention was completed.

That is, according to the present invention, the above objects and advantages of the present invention are (A) hyaluronic acid and / or hyaluronic acid salt, and (B) polycarboxylic acid and its salt, polyol, sugar and amino acid, and An ophthalmic surgery comprising an aqueous solution containing at least one viscosity stabilizer selected from the group consisting of salts thereof and having a viscosity at 37 ° C. of not less than 2,000 centipoise and less than 20,000 centipoise. Achieved by supplements.

The hyaluronic acid used in the present invention preferably has a number average molecular weight in the range of 600,000 to 3.9 million. As the salts of hyaluronic acid, sodium salts, potassium salts, basic amino acid salts and the like are used. Among them, sodium salts are particularly preferable for preparations used for ophthalmic surgery, in view of the vitreous body composition and the salt composition of aqueous humor. The concentration of hyaluronic acid and its salt in the aqueous solution preparation of the present invention is appropriately determined according to the viscosity for the purpose of use, but is preferably 0.5 to 5.0% by weight.
In the range.

The viscosity stabilizers used in the present invention are polycarboxylic acids and salts thereof, polyols, carbohydrates and amino acids and salts thereof. These can be used alone or in combination of two or more. These viscosity stabilizers are water-soluble and contribute to the stabilization and thickening of the aqueous solution of the present invention. In the present invention, the viscosity stability test with time was evaluated by measuring the viscosity or the intrinsic viscosity.

As the polycarboxylic acid and its salt, sodium citrate and carboxyvinyl polymer are preferably used. These can be used alone or in combination. The polycarboxylic acids and salts thereof are preferably used at a concentration of 0.05 to 1.0% by weight.

[0015] As the polyol, ethylene glycol, propylene glycol, glycerin, polyvinyl alcohol and polyethylene glycol are preferably used. These can be used alone or in combination of two or more. The polyol is preferably used in a concentration of 0.5 to 10.0% by weight, more preferably 1.0 to 2.5% by weight.

As saccharides, sorbitol, trehalose, sucrose, carboxymethylcellulose and β-cyclodextrin are preferably used. These can be used alone or in combination of two or more. The carbohydrate is preferably used at a concentration of between 0.05 and 5.0% by weight.

Histidine, arginine and sodium aspartate are preferably used as amino acids. These can be used alone or in combination of two or more. The amino acid is used at a concentration of 0.05 to 1.0% by weight.

The aqueous solution of the present invention contains hyaluronic acid and / or
Alternatively, it is prepared by dissolving sodium hyaluronate (A) and a viscosity stabilizer (B) in an aqueous catalyst. As the aqueous medium, purified water, an aqueous solution in which an isotonic agent is dissolved, or an aqueous solution in which a buffer is dissolved are preferably used. The tonicity agent or buffer is preferably prepared by dissolving it in purified water at 2% by weight or less.

As the tonicity agent, sodium chloride and potassium chloride are preferred. Examples of the buffer include phosphate buffers such as sodium dihydrogen phosphate and sodium monohydrogen phosphate, borate buffers such as borax and boric acid, and Tris buffers such as trisaminomethane and dilute hydrochloric acid and trismalate and dilute caustic soda solution. Agents are preferred.
The pH range of the aqueous solution of the present invention is preferably from pH 6 to pH 8. In the acidic region of pH 6 or lower or the alkaline region of pH 8 or higher, hydrolysis greatly reduces the viscosity, and should be avoided. Further, the osmotic pressure of the aqueous solution of the present invention,
When the concentration of the isotonicity agent is adjusted and physiological saline is set to 1, it is preferable that the osmotic pressure ratio falls within the range of 0.7 to 1.3.

According to the present invention, a stability test of the thus obtained stabilized preparation was conducted, and as a result, assuming that the initial value of the viscosity (or intrinsic viscosity) was 100%, it was 3 months at 40 ° C. Since it showed a viscosity retention rate of 90% or more when it was stored, and the stability was remarkably obtained compared to the viscosity decrease of the comparative example without a stabilizer (Tables 5 and 6), it was stored for a long time at room temperature. It has become possible. Further, in a high temperature test at 100 ° C. for 20 minutes, the formulation also showed a viscosity retention rate of 90% or more, which enabled one-step heat sterilization.

The viscosity range of the aqueous solution of the present invention is 2,000 or more and 20,000 cps at 37 ° C., which is the optimum temperature of the auxiliary agent used in cataract surgery, intraocular lens transplant surgery, glaucoma surgery and full thickness corneal transplant surgery. Is less than the intrinsic viscosity of less than about 16 to 35 dl / g. A desired viscosity preparation can be easily prepared by appropriately selecting the molecular weight of hyaluronic acid and its concentration, the type of thickener (viscosity stabilizer) and its concentration.

As an example, as shown in Table 1 below, 1.0% by weight of sodium hyaluronate having an average molecular weight of 1,000,000 is used.
The average viscosity of concentration is 3100 before heat treatment without thickener.
In contrast to cps, by adding 2.0% by weight of propylene glycol as a thickening agent to this solution, the viscosity could be increased to 4200 cps before heat treatment. Other polycarboxylic acids, polyols, sugars and amino acids also showed thickening effects.

[0023]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Example 1 1% by weight of hyaluronic acid sodium salt (molecular weight 1,000,000) was dissolved in a physiological phosphate buffer solution containing propylene glycol at 0, 0.5, 1, 2, 3, 4% by weight, and each solution was dissolved. It measured at a shear rate of 4 / sec using a rotational viscometer. The result is shown in FIG. As seen in FIG. 1, it is clear that the addition of propylene glycol thickens the aqueous solution of sodium hyaluronate.

Example 2 and Comparative Example 1 Hyaluronic acid sodium salt (molecular weight 1,000,000) was added to a physiological phosphate buffer containing 2% by weight of propylene glycol.
Was dissolved in 1% by weight, and then heat treated at 100 ° C.
After the heat treatment for 10 minutes and the heat treatment for 20 minutes, the viscosity was measured using a rotational viscometer at a shear rate of 4 / sec. Table 1 shows the measured values and the viscosity retention ratio when the viscosity before heat treatment was taken as 100%. As a control, the same measurement was carried out for the sample to which propylene glycol was not added.

[0025]

[Table 1]

The results in Table 1 also show that the addition of propylene glycol can suppress the decrease in viscosity of the aqueous sodium hyaluronate solution.

Example 3 and Comparative Example 2 Hyaluronic acid sodium salt (1 million in molecular weight) was dissolved by 1% by weight in a physiological phosphate buffer containing 0.075% by weight of carboxyvinyl polymer, followed by heat treatment at 100 ° C. Before the heat treatment, after 10 minutes of heat treatment, and after 20 minutes of heat treatment, the viscosity was measured at a shear rate of 4 / sec using a rotational viscometer. Table 2 and FIG. 2 show the measured values and the viscosity retention rate when the viscosity before heat treatment was 100%. In addition, as a control, the same measurement was performed for the sample to which the carboxyvinyl polymer was not added.

[0028]

[Table 2]

From the results shown in Table 2 and FIG. 2, it is understood that the addition of the carboxyvinyl polymer can suppress the decrease in viscosity of the sodium hyaluronate aqueous solution and increase the viscosity.

Example 4 and Comparative Example 3 Hyaluronic acid sodium salt (molecular weight: 1,000,000) was dissolved in a physiological phosphate buffer solution containing 1% by weight of trehalose in an amount of 1% by weight, followed by heat treatment at 100 ° C. After the heat treatment for 10 minutes and the heat treatment for 20 minutes, the viscosity was measured using a rotational viscometer at a shear rate of 4 / sec. Table 3 shows the measured values and the viscosity retention rate when the viscosity before heat treatment was 100%.
As a control, the same measurement was performed for the sample to which trehalose was not added.

[0031]

[Table 3]

The results in Table 3 also show that the addition of trehalose can suppress the decrease in viscosity of the sodium hyaluronate aqueous solution.

Example 5 and Comparative Example 4 Hyaluronic acid sodium salt (molecular weight: 1 was added to a physiological phosphate buffer containing 0.3% by weight of carboxymethyl cellulose).
1,000,000% by weight was melted and then heat treated at 100 ° C. The viscosity before heat treatment, after 10 minutes heat treatment, and after 20 minutes heat treatment was measured at a shear rate of 4 / sec using a rotational viscometer. Table 4 shows the measured values and the viscosity retention rate when the viscosity before heat treatment is 100%. As a control, the same measurement was carried out for the sample to which carboxymethyl cellulose was not added.

[0034]

[Table 4]

The results in Table 4 also show that the addition of carboxymethyl cellulose can suppress the decrease in viscosity of the sodium hyaluronate aqueous solution.

Example 6 and Comparative Example 5 Hyaluronic acid sodium salt (molecular weight 1,000,000) was added to a physiological phosphate buffer containing 2% by weight of propylene glycol.
Was dissolved in 1% by weight, and after heat treatment at 100 ° C. for 20 minutes, 4
Stored at 0 ° C and 75% relative humidity, immediately after storage 1
After 3 months, the viscosity after 3 months of storage was measured at a shear rate of 4 / sec using a rotational viscometer. Table 5 shows the measured values and the viscosity retention ratio when the viscosity immediately after storage was taken as 100%. In addition,
As a control, the same measurement was performed for the sample to which propylene glycol was not added.

[0037]

[Table 5]

The results in Table 5 also show that the addition of propylene glycol can suppress the decrease in viscosity of the aqueous sodium hyaluronate solution.

Example 7 and Comparative Example 6 Hyaluronic acid sodium salt (molecular weight: 2250,000) was added to a physiological phosphate buffer containing 2% by weight of propylene glycol.
Was dissolved in 1% by weight, and after heat treatment at 100 ° C. for 20 minutes, 4
Stored at 0 ° C and 75% relative humidity, immediately after storage 1
After 6 months and 3 months of storage, the intrinsic viscosity was measured, and the measured values and the viscosity retention rate when the viscosity immediately after storage was taken as 100% are shown in Table 6.
FIG. As a control, the same measurement was carried out for the sample to which propylene glycol was not added.

[0040]

[Table 6]

As can be seen from Table 6 and FIG. 3, addition of propylene glycol can suppress the lowering of the molecular weight of hyaluronic acid in the aqueous solution of sodium hyaluronate.

[0042]

INDUSTRIAL APPLICABILITY The present invention provides a relatively stable solution by adding a specific polycarboxylic acid and its salt, a polyol, a sugar and an amino acid, which are viscosity stabilizers, to an aqueous solution of hyaluronic acid and / or its salt. A viscous hyaluronic acid preparation can be prepared, and therefore, the product can be stably stored at room temperature for a long period of time and can be sterilized by one-step heating. In addition, the stabilizer also has a thickening effect and was able to thicken the low-viscosity preparation, thereby enhancing the intraocular space forming ability of the preparation.

[Brief description of drawings]

FIG. 1 shows the relationship between the propylene glycol content and the viscosity of an aqueous sodium hyaluronate solution.

FIG. 2 shows the relationship between the heat treatment time and the viscosity of the aqueous solutions of Examples of the present invention and the comparative aqueous solution.

FIG. 3 shows the relationship between the aging time and the viscosity of an aqueous solution of an example of the present invention and a comparative aqueous solution.

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[Procedure amendment]

[Submission date] October 22, 1996

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction contents]

The chemical structure of sodium hyaluronate consists of sodium glucuronate and N- acetylglucosamine in β.
It is a high molecular polysaccharide having repeating units of 1 → 3 and β1 → 4 linkage. The substance is distributed in mammalian cartilage, connective tissues such as joints, the vitreous body of the eye, and the corolla. In recent years, the substance can be obtained by producing microorganisms such as Streptococcus. Natural sodium hyaluronate is
When present in a living body, its average molecular weight is 8,000,000 to 1
It is said to be 3 million, and its molecular weight range is usually 20,000-40 because it undergoes lower molecular weight one after another during its isolation and purification.
100,000 products will be available.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Correction contents]

The powdery substance, when used for the above-mentioned intended use, must be dissolved in physiological saline, phosphoric acid type, boric acid type and Tris buffer . However, the hyaluronic acid in such an aqueous solution state is gradually degraded at room temperature and rapidly under heating conditions, and the viscosity (or intrinsic viscosity) is also reduced accordingly. Therefore, most of the products on the market have to be stored in a cool and dark place for a long period of time, and the labor and distribution cost at the time of product distribution cannot be ignored. Further, the heat sterilization operation, which is important in the formulation process, is complicated, such as the intermittent sterilization method, and many precautions are required to prevent lowering of the molecular weight of the main component.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0010

[Correction method] Change

[Correction contents]

[0010]

The inventors of the present invention have conducted a search for a stabilizer to solve the above problems, and as a result, have found that an aqueous solution containing hyaluronic acid or a salt thereof contains a specific polycarboxylic acid or polyol. Low in carbohydrates and amino acids
It was also found that the addition of one kind of the solution suppresses the lowering of the viscosity of the aqueous solution and exhibits the viscosity stability at room temperature and under heating for a long period of time , and the stabilizer also has a thickening effect .
Then, a thickened preparation of hyaluronic acid aqueous solution was prepared, and the present invention was completed.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction contents]

The aqueous solution of the present invention contains hyaluronic acid and / or
Alternatively, it is prepared by dissolving sodium hyaluronate (A) and a viscosity stabilizer (B) in an aqueous medium . As the aqueous medium, purified water, an aqueous solution in which an isotonic agent is dissolved, or an aqueous solution in which a buffer is dissolved are preferably used. The tonicity agent or buffer is preferably prepared by dissolving it in purified water at 2% by weight or less.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 47/26 A61K 47/26 J 47/32 47/32 J (72) Inventor Yasushi Takahashi Kanagawa 410-6 Shimozomi, Sagamihara-shi, Japan

Claims (5)

[Claims] 1. At least one viscosity stabilizer selected from the group consisting of (A) hyaluronic acid and / or hyaluronic acid salt, and (B) polycarboxylic acid and its salt, polyol, sugar and amino acid and its salt. An auxiliary agent for eye surgery, which comprises an aqueous solution containing an agent and having a viscosity at 37 ° C. of not less than 2,000 centipoise and less than 20,000 centipoise. 2. The aid for ophthalmic surgery according to claim 1, wherein the polycarboxylic acid and its salt are selected from the group consisting of sodium citrate and carboxyvinyl polymer. 3. The ophthalmic adjuvant according to claim 1, wherein the polyol is selected from the group consisting of ethylene glycol, propylene glycol, glycerin, polyvinyl alcohol and polyethylene glycol. 4. The method according to claim 1, wherein the saccharide is selected from the group consisting of sorbitol, trehalose, sucrose, carboxymethylcellulose, and β-cyclodextrin. 5. The adjuvant for ophthalmic surgery according to claim 1, wherein the amino acid is selected from the group consisting of histidine, arginine and sodium aspartate.